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LSD1 inhibition promotes epithelial differentiation through derepression of fate- determining transcription factors [ChIP-seq]

ABSTRACT: We report the impact of the pharmacological inhibition of the Histone 3 Lysine 4 demethylase (H3K4) LSD1 (KDM1A) enzymatic activity on its binding genome wide and how it impacts genome-wide H3K4me1 and H3K4me2 deposition in Normal Human Epidermal Keratinocytes (NHEK)

ORGANISM(S): Homo sapiens

PROVIDER: GSE133560 | GEO | 2019/08/20

REPOSITORIES: GEO

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LSD1 inhibition promotes epithelial differentiation through derepression of fate- determining transcription factors [inhibitors]

Project description:We report the impact of the pharmacological inhibition of the Histone 3 Lysine 4 demethylase (H3K4) LSD1 (KDM1A) enzymatic activity on genome-wide gene expression in normal human epidermal keratinocyte (NHEK)

2019-08-20 | GSE133737 | GEO

Histone Demethylase Lsd1 is Required to Repress Hematopoietic Stem and Progenitor Cell Signatures During Blood Cell Maturation

Project description:Here we describe that lysine-specific demethylase 1 (Lsd1/KDM1a), which demethylates histone H3 on LysM-bM-^@M-^I4 or LysM-bM-^@M-^I9 (H3K4/K9), is an indispensible epigenetic governor of hematopoietic differentiation. Integrative genomic analysis in primary hematopoietic cells, combining global occupancy of Lsd1, genome-wide analysis of its histone substrates H3K4 mono- and di-methylation and gene expression profiling, reveals that Lsd1 represses hematopoietic stem and progenitor cell (HSPC) gene expression programs during hematopoietic differentiation. We found that Lsd1 function was not restricted to transcription start sites, but is also critical at enhancers. Loss of Lsd1 at these sites was associated with increased H3K4me1 and H3K4me2 methylation levels on HSPC genes and their derepression. Failure to fully silence HSPC genes compromised differentiation of hematopoietic stem cells and mature blood cell lineages. Our data indicate that Lsd1-mediated concurrent repression of enhancer and promoter activity of stem and progenitor cell genes is a pivotal epigenetic mechanism required for proper hematopoietic maturation. To identify direct target genes of Lsd1 in myeloid cells we mapped global occupancy of Lsd1 in 32D granuolocytic progenitor cells and compared H3K4me1/me2/me3 and H3K27ac histone modifications in Lsd1fl/fl (wild type) vs. Lsd1fl/f Mx1Cre (knockout) Gr1dim Mac1 granuolocytic progenitor cells.

2013-06-25 | E-GEOD-40440 | biostudies-arrayexpress

GR and LSD1/KDM1A-targeted gene activation requires selective H3K4me2 demethylation at enhancers

Project description:KDM1A-mediated H3K4 demethylation is a well-established mechanism underlying transcriptional gene repression, but its role in gene activation is less clear. Here we report a critical function and novel mechanism of action of KDM1A in glucocorticoid receptor (GR)-mediated gene transcription. Biochemical purification of the nuclear GR complex revealed KDM1A as an integral component. In cell-free assays, GR modulates KDM1A-catalyzed H3K4 progressive demethylation by limiting loss of H3K4me1. Similarly, in cells KDM1A binds to most GR binding sites where it removes preprogrammed H3K4me2 but leaves H3K4me1 untouched. Blocking KDM1A catalytic activity prevents H3K4me2 removal, severely impairs GR binding to chromatin, and dysregulates GR-targeted genes. Taken together, these data suggest KDM1A-mediated H3K4me2 demethylation at GRBSs promotes GR binding and plays an important role in glucocorticoid-induced gene transcription, offering a new mechanism contributing to nuclear receptor mediated gene activation.

2020-04-04 | GSE108588 | GEO

Histone Demethylase Lsd1 is Required to Repress Hematopoietic Stem and Progenitor Cell Signatures During Blood Cell Maturation

Project description:Here we describe that lysine-specific demethylase 1 (Lsd1/KDM1a), which demethylates histone H3 on Lys 4 or Lys 9 (H3K4/K9), is an indispensible epigenetic governor of hematopoietic differentiation. Integrative genomic analysis in primary hematopoietic cells, combining global occupancy of Lsd1, genome-wide analysis of its histone substrates H3K4 mono- and di-methylation and gene expression profiling, reveals that Lsd1 represses hematopoietic stem and progenitor cell (HSPC) gene expression programs during hematopoietic differentiation. We found that Lsd1 function was not restricted to transcription start sites, but is also critical at enhancers. Loss of Lsd1 at these sites was associated with increased H3K4me1 and H3K4me2 methylation levels on HSPC genes and their derepression. Failure to fully silence HSPC genes compromised differentiation of hematopoietic stem cells and mature blood cell lineages. Our data indicate that Lsd1-mediated concurrent repression of enhancer and promoter activity of stem and progenitor cell genes is a pivotal epigenetic mechanism required for proper hematopoietic maturation.

2013-06-25 | GSE40440 | GEO

Effect of LSD1 knockdown on histone H3K4 methylation in HEL human erythroleukemia cell line.

Project description:To understand the role of LSD1 in regulating histone H3K4 methylation status, ChIP-seq analyse of mono- and di-methylated H3K4 in LSD1-KD HEL cells were performed. The analyses revealed demethylation of H3K4me1 and H3K4me2 by LSD1 at regulatory regions including CEBPA gene enhancer.

2021-05-04 | GSE145399 | GEO

ChIP-sequencing of the H3K4me1/2 in crypts from mice intestinal epithelium with intestinal epithelium specific LSD1 knock out compared to wild type

Project description:To study the epigenetic regulation of intestinal epithelium we focus on the role of chromatin modulators. Lysine-specific histone demethylase 1a (KDM1A, LSD1) is one of the enzymes that can erase the H3K4me1/2 mark. To assess the role of LSD1 in intestinal epithelium we studied wild type (WT) (Villin-Cre -; Lsd1f/f) and intestinal-epithelial-specific knock-out (KO) (Villin-Cre+; Lsd1f/f) mice. We found that KO mice completely lack Paneth cells, and have altered stem cell characteristics compared to WT littermates. To assess genome-wide H3K4me1/2 levels in WT and KO small intestines, we sorted small intestinal crypt cells, fixed them, isolated chromatin, and performed ChIP using an H3K4me1 and an H3K4me2 antibody as described in the protocols.

2020-11-16 | E-MTAB-7871 | biostudies-arrayexpress

EBF2 links KMT2D-mediated H3K4me1 to suppress pancreatic cancer progression via upregulating KLLN [RNA-seq]

Project description:We sought to elucidate the roles of KMT2D- and EBF2-regulated H3K4me1 in gene expression through profiling the gene transcription in PDAC cells overexpressed with EBF2 (EBF2-OE) or activated by GSK-LSD1, a selective inhibitor of KDM1A/LSD1 which can increase H3K4me1 level via blocking the histone H3K4 demethylase activity of KDM1A/LSD1

2023-07-18 | GSE237363 | GEO

ChIP-seq analysis of gene expression regulated by LSD1 in CD8+ T cells

Project description:ChIP-seq assay was performed with GSK- or Vehicle-treated CD8+ T cells to interrogate the genome-wide distribution of LSD1, H3K4me1, H3K4me2, H3K4me3, H3K27ac, and Pol II, and their alterations in response to LSD1 inhibition.

2024-04-24 | GSE248891 | GEO

Lysine-Specific Demethylase 1 Has Dual Functions as a Major Regulator of Androgen Receptor Transcriptional Activity

Project description:Lysine Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4), but has coactivator function on some genes through unclear mechanisms. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at these sites. These findings show LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and has a distinct AR-linked coactivator function mediated by demethylation of other substrates. Determine the role of LSD1 in androgen signaling.

2014-12-12 | E-GEOD-52201 | biostudies-arrayexpress

ATAC-sequencing mice small intestinal epithelium with intestinal epithelium specific LSD1 knock out compared to wild type

Project description:To study the epigenetic regulation of intestinal epithelium we focus on the role of chromatin modulators. Lysine-specific histone demethylase 1a (KDM1A, LSD1) is one of the enzymes that can erase the H3K4me1/2 mark. To assess the role of LSD1 in intestinal epithelium we studied wild type (WT) (Villin-Cre -; Lsd1f/f) and intestinal-epithelial-specific knock-out (KO) (Villin-Cre+; Lsd1f/f) mice. We found that KO mice completely lack Paneth cells, and have altered stem cell characteristics compared to WT littermates. To assess genome-wide ATAC levels in WT and KO small intestines, we isolated intestinal epithelium tissue from wild type mice and LSD1 KO mice. This tissue was digested to single cells and performed ATAC seq as described in the protocols.

2021-03-23 | E-MTAB-8718 | biostudies-arrayexpress

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